The purpose of this Career Development Award (CDA-2) application is to facilitate Dr. Jacob Lindheimer's transition from a new investigator of chronic, multi-symptom illnesses (CMI) into an independent translational investigator in the VA Healthcare System. The specific focus of this CDA-2 is on studying aerobic exercise intolerance in a prevalent and debilitating CMI known as Gulf War Illness. Dr. Lindheimer is an integrative psycho-physiologist with a background in the field of exercise science and is currently a Post-Doctoral Fellow at the War Related Illness and Injury Study Center of the VA New Jersey Healthcare System. He works closely with his co-mentors, Drs. Dane Cook and Michael Falvo, on a multi-site Merit Review study of patho- physiological mechanisms in GWI. This CDA-2 will allow Dr. Lindheimer to obtain additional skills in (1) clinical trials and biostatistics, (2) analysis and interpretation of immunological assay data, and (3) clinical exercise physiology testing. An additional training goal is for Dr. Lindheimer to continue developing the neuroimaging skills that he acquired during his post-doctoral fellowship training. Neuroimaging will not be used as an outcome measure in the proposed research, but will be an essential component of a subsequent Merit Review application in Year 5 of this CDA-2. The overall goal of the research plan is to provide critical information for developing an exercise prescription that is tolerable for Veterans with GWI. To that end, a novel and innovative study design has been developed to measure the dose-response relationship between aerobic exercise intensity and a pervasive phenomenon that affects CMI populations (e.g., Gulf War Illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Fibromyalgia) known as post-exertion malaise (PEM). Although it is clear that aerobic exercise can induce PEM, the specific features of exercise that elicit PEM are not. A within-subjects, randomized, controlled, crossover study will test the effect of light- moderate- and vigorous exercise on symptomatic, behavioral and biological indices of PEM in a sample of Veterans with GWI (n=40). Our central hypothesis is that is that there will be a dose-dependent, relationship between exercise intensity and PEM, which is manifested by: increases in GWI symptom severity (Aim 1), increases in pain sensitivity (Aim 1), decreases in cognitive performance (Aim 1), up-regulation of pro-inflammatory and regulatory cytokines (i.e., IL-6, IL-8, IL-10, TNF-?) (Aim 2), decreases in physical activity behavior (Aim 3), and increases in sedentary behavior (Aim 3). Validated questionnaires will be used to measure GWI symptoms. Pain sensitivity will be measured with psycho-physical procedures used to determine perceptual responses to a range of thermal stimuli. Cognitive performance will be measured with a computerized version of the Paced Auditory Serial Addition Task. Pro-inflammatory cytokines will be measured by multi-cytokine array using an electrochemiluminescence platform. Physical activity and sedentary behavior will be measured via accelerometry. Participants will complete an initial familiarization lab visit, followed by four additional experimental visits. All measures in Aims 1 and 2 will be administered immediately before and after 20 minutes of aerobic cycling exercise. Aim 3 measures will take place for one-week following each experimental visit. Following one week of physical activity monitoring and an additional week of recovery (two weeks total), participants will return to the lab to complete subsequent experimental visits. Dr. Lindheimer will use the findings from this study to develop an evidence based exercise prescription for preventing symptomatic, behavioral and biological consequences of PEM in Veterans with GWI. Using the data collected from this study and the skills and experiences obtained from the rigorous career development plan that Dr. Lindheimer and his mentoring team have developed, the efficacy of this evidence based exercise prescription will be tested in a Merit Review investigation focused on a broader range of Veterans with CMIs.